L-alpha-acetylmethadol (LAAM) is one of a group of drugs which has been found to form inhibitory complexes with the hepatic enzymes responsible for their biotransformation. Such drugs also include SKF 525-A, propoxyphene, and amphetamine derivatives. The formation of these cytochrome P-450-metabolic intermediate complexes inhibits the metabolism of the drugs themselves, as well as the metabolism of other drugs, especially narcotics, where the main route of biotransformation is oxidative metabolism. In addition to the formation of these complexes in the in vitro system using microsomal fractions, they have been observed in whole animal and isolated perfused liver studies with SKF 525-A, propoxyphene and LAAM. This research project is designed to elucidate the mechanism of formation and nature of these cytochrome P-450-metabolic intermediate complexes, and the factors controlling their formation in isolated hepatocytes, isolated perfused liver and lung, and whole animal as compared to microsomal fractions. Their inhibitory effect on the metabolism of the parent and other drugs in the various artificial systems and whole animal will be investigated as a means of anticipating the pharmacological effects of MI complexes in drug abuse situations and during rational drug therapy.